Combined herbal and pharmaceutical composition and method

ABSTRACT

An herbal combination composition can include, herbal extracts, including combinations of: Hyssopus officinalis, Zingiber officinale, Viola odorata, Ziziphus jujuba, Chamomile, and Ocimum tenuiflorum; pharmaceutical compositions, including combinations of: dextromethorphan, guaifenesin, acetaminophen, phenylephrine, diphenhydramine; polyethylene glycol; propylene glycol; poloxamer 407; ethylenediaminetetraacetic acid; methyl paraben; potassium sorbate; propyl paraben; xanthan gum; citric acid; anhydrous citric; and purified acetate buffered water. Also disclosed is a method for manufacture of an herbal combination composition, including dissolving herbal extracts, adding poloxamer, adding pharmaceutical compositions, adding acetate buffer, adding xanthan gum gel, adding acetate buffer.

CROSS-REFERENCE TO RELATED APPLICATIONS

N/A

FIELD OF THE INVENTION

The present invention relates generally to the field of herbal medicinesand remedies, and more particularly to methods and formulation forcombining herbal extracts with conventional pharmaceutical compositions.

BACKGROUND OF THE INVENTION

The continuously growing herbal use in international market shows thebeneficial use of herbal medicines as a complement to generalpharmaceuticals. This situation has left consumers to wander aroundshelves to self-select different herbal and pharmaceutical supplementsand medications separately, as they are in many cases not available onthe same shelf of the same store. Patients struggle to get a goodsynergistic combination of herbal and pharmaceuticals; as in most casesthere are no combinations available in ready-made combined forms. Mostof the time consumers/patients remain unsuccessful in diminishing theirailment related sufferings and pain, which could be possible by usingthe benefits of both herbal medicines and conventional pharmaceuticalsin a single formulation.

Combining herbals with pharmaceuticals is not a trivial undertaking interms of product quality, consistency, and shelf life. Herbal extractsare not comprised of single molecule but are rather composed of avariety of molecules of different pharmaceutical classes. Herbalextracts constitute combinations of enzymes, co-enzymes, catalysts,volatile, fixed oils, flavonoids, amino acids, complexing agents,saponins, triterpinoids, tannins, sesquiterpenes, monoterpenes, etc.These chemical moieties are in many cases reactive to the activepharmaceuticals and cause their degradation in a small period of time,resulting in separation of layers, suspension, turbidity, discoloration,and in some cases change of the active pharmaceuticals into a toxicmaterial.

This complex situation needs a pre-study of the compatible herbalsselection, optimization of the quantity added of each herbal extractbesides the addition of formulation excipients such as solubilizes,flavors, humectants, sweetening agents, and preservatives to the activepharmaceuticals; so that a stable formulation can be achieved.

Combining herbals with pharmaceuticals is not always successful but needto be proven by the results of a detailed chemical and microbiologicalstability studies. United States pharmacopeia provides acceptancecriteria in terms of potency of the active pharmaceuticals, and theabsence of microbiological growth during the label claimed shelf life.The average shelf life for a liquid formulation is eighteen months.During the shelf life product must maintain its physicochemicalattributes within USP acceptance criteria. Shelf stability is not onlyimportant but a robust manufacturing technique with detailed steps isrequired to avoid complexation, suspension, loss of flavoring agents,volatiles, mixing of oils with water, avoiding complexation leading toprecipitation, separation of layers, etc.

As such, considering the foregoing, it may be appreciated that therecontinues to be a need for novel and improved devices and methods forcombining herbal extracts with pharmaceutical compositions.

SUMMARY OF THE INVENTION

The foregoing needs are met, to a great extent, by the presentinvention, wherein in aspects of this invention, enhancements areprovided to the existing model of combining herbal extracts withpharmaceutical compositions.

Aspects of this invention provide combined/fused formulations of singletherapies of medicinal herbal extracts and synergistic cold and coughpharmaceuticals.

Another aspect of this invention also defines a detailed stepwise methodof manufacturing ensuring reproducibility of the end products with thesame physicochemical attributes. The invented product maintainsmicrobiological as well as chemical quality, meeting all standards ofthe current United States Pharmacopeia (USP) during its label claimedshelf life.

In yet another aspect, this invention is also coupled with the inventionof a new single robust analytical method to analyze potency of all ofthe individual active ingredients in the presence of herbal actives. Themethod is capable of identifying and quantifying active pharmaceuticalswithin complex composition of the formulation in significantly lowretention time and high resolution as compared to many othermethods/combination of methods reported in literature for differentactive ingredients.

In related aspects, this invention is furnishing new knowledge in termsof manufacturing technique, selection of herbs, compatibility of herbswith active pharmaceutical ingredients of formulation by utilizing newlyinvented robust analytical methods as elements of the entire innovation.

In other related aspects, the usefulness of invention hinges on bringingthe benefits of the fused/combined medicinal herbal and pharmaceuticalsformulations therapy to the population suffering from common cold,influenza, seasonal allergies, etc.

In an aspect, an herbal combination composition, can include:

-   -   a) herbal extracts, including at least one or a combination of:        Hyssopus officinalis; Zingiber officinale; Viola odorata;        Ziziphus jujuba; Chamomile; Ocimum tenuiflorum; and    -   b) pharmaceutical compositions, including at least one or a        combination of: Dextromethorphan; Guaifenesin; Acetaminophen;        Phenylephrine hydrochloride; Diphenhydramine hydrochloride.

In an aspect, a method for manufacture of an herbal combinationcomposition can include:

-   -   a) dissolving herbal extracts;    -   b) adding poloxamer;    -   c) adding pharmaceutical compositions;    -   d) adding acetate buffer;    -   e) adding xanthan gum gel; and    -   f) adding acetate buffer.

There has thus been outlined, rather broadly, certain embodiments of theinvention in order that the detailed description thereof herein may bebetter understood, and in order that the present contribution to the artmay be better appreciated. There are, of course, additional embodimentsof the invention that will be described below and which will form thesubject matter of the claims appended hereto.

In this respect, before explaining at least one embodiment of theinvention in detail, it is to be understood that the invention is notlimited in its application to the details of construction and to thearrangements of the components set forth in the following description orillustrated in the drawings. The invention is capable of embodiments inaddition to those described and of being practiced and carried out invarious ways. In addition, it is to be understood that the phraseologyand terminology employed herein, as well as the abstract, are for thepurpose of description and should not be regarded as limiting.

As such, those skilled in the art will appreciate that the conceptionupon which this disclosure is based may readily be utilized as a basisfor the designing of other structures, methods and systems for carryingout the several purposes of the present invention. It is important,therefore, that the claims be regarded as including such equivalentconstructions insofar as they do not depart from the spirit and scope ofthe present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flowchart illustrating steps that may be followed, inaccordance with one embodiment of a method or process of manufacture ofan herbal combination composition.

DETAILED DESCRIPTION

Before describing the invention in detail, it should be observed thatthe present invention resides primarily in a novel and non-obviouscombination of elements and process steps. So as not to obscure thedisclosure with details that will readily be apparent to those skilledin the art, certain conventional elements and steps have been presentedwith lesser detail, while the drawings and specification describe ingreater detail other elements and steps pertinent to understanding theinvention.

The following embodiments are not intended to define limits as to thestructure or method of the invention, but only to provide exemplaryconstructions. The embodiments are permissive rather than mandatory andillustrative rather than exhaustive.

In the following, we describe the structure of various embodiments of anherbal combination composition and methods for its manufacture.

In various embodiments, the herbal combination composition can be amixture, including a powder, which can be a granule powder; a syrup,emulsion, or suspension with an established viscosity, color, pH andflavors. Oily parts must be dispersed into fine globules within syrupwith the help of an emulsifying agent. Therefore, an acceptableformulation cannot be achieved simply by a juice mixer technique. Itneeds step wise control and testing during manufacturing till a stableformulation is achieved for a shelf life stability testing at varioustemperatures and relative humidity to mimic shelf life conditions ofdifferent countries. Higher temperature and relative humidity study isan alternative to have an accelerated study for a short period of timeto apply a linear regression for the extrapolated time period. Oncestudies are successfully completed, then the data is considered as thenew knowledge to satisfy the claim labels of the active pharmaceuticalsin the mixed formulation.

In related embodiments, microbial and fungal contamination control ofthe herbs are other major challenges as the source of the herbs arenatural agricultural fields rather than a controlled manufacturing of achemical plant. A specific preservative or a combination ofpreservatives in the correct quantities needs to be selected andemployed based on the incoming quality of raw herbal extracts from theextract manufacturers; to avoid any fungal or microbial growth in thecombined formulation.

In further related embodiments, in order to make stable formulations theparticulate size of the herb extracts needs to be maintained andparticles larger than 0.5 micron needs to be eliminated by filtration toavoid suspension, and segregation.

In other further related embodiments, solubilizing different moieties ofthe extracts is not as simple as one or few molecules of the activepharmaceuticals. It needs the use of co-solvents, solubilizes, chelatingagents, emulsifying agents and experimenting those until an optimizedcombination is satisfied. A new knowledge establishes here as the partof the invention.

In further related embodiments, an herbal combination composition caninclude chelating agents, co-solvents, preservatives, solubilizes, andother excipients. Polyethylene glycol 1000, or PEG 600-1000, can beincluded to thicken a syrup with Xanthan gum to establish a targetviscosity of the syrup.

In a further related embodiment, an acetate buffer and/or citric acidcan be used to maintain pH of the herbal combination composition around5.0.

In further related embodiments, a high shear mixing technique can beused to produce a homogenized solution, such as shown in the processflow diagram depicted in FIG. 1. Heating/Cooling and RPM of theagitators can be varied to adjust the process and hot water jacketedheating and cooling can be configured at different levels of themanufacturing as defined in the process flow diagram shown in FIG. 1.

In a related embodiment, the herbal combination composition can beformulated for diabetic patients, such that the herbal combinationcomposition includes artificial non sugar based sweetener, such assaccharine sodium, sucralose, etc.

In various embodiments, the herbal combination composition can includeHyssop, Ginger, Viola odorta, jujube, chamomile, Holy Basil (Ocmiumtenuiflorum), having the following characteristics:

-   -   a) Hyssopus officinalis (Hyssop) has been indicated in the        Natural Medicines for cough, common cold, respiratory        infections, and sore throat. It is considered GRAS (generally        recognized as safe) by the US Food and Drug Administration;    -   b) Zingiber officinale (Ginger) is reported as GRAS by the FDA.        It has been indicated in the natural medicines for upper        respiratory tract infections, cough, bronchitis, nausea, and        headache. The active part of ginger is ginger root. It includes        gingerol, gingerdione, shogaol, sesquiterpine, and monoterpene        volatile oils.    -   c) Viola odorata (Sweet violet) is indicated in the natural        medicines for chronic and acute bronchitis, bronchial asthma,        acute and chronic mucous inflammation, cold symptom hoarseness,        chest spastic and whooping cough;    -   d) Ziziphus jujuba (Jujube or red date) is indicated for cold        and cough; especially the calming nature has reported providing        stress relief, and promoting sleep;    -   e) Chamomile, which can include extracts of various species of        Asteraceae, is reported as GRAS by the FDA. Chamomile extract        has been indicated for respiratory tract irritation, allergic        rhinitis, and nasal membrane inflammation;

f) Holy Basil (Ocimum tenuiflorum) has been indicated for its short term(4 to 6 weeks) use as a safe remedy for common cold, influenza, swineflu, asthma, bronchitis, and fever because of its anti-infectiveproperties.

In related embodiments, a detailed scientific review of the herbalconstituents has provided support for selecting and optimize these herbsin the range of 1-2% individually of the clinical dose, not exceedingmore than 7% of the total herbal content. Formulation was put on a longterm stability study at 25±2 degree Celsius and relative humidity of60±5% as required by United States Pharmacopeia. The label claimedpotency was found within 110% and 90% of the label claim at 21 monthslong term samples.

Development and research of related embodiments, led to development of arobust analytical spectroscopic High Pressure Liquid Chromatographymethod to test each sample for all active pharmaceuticals in thepresence of all herbal constituents and excipients with highest clearresolution of each individual active ingredient. The overlapping peaksof many unknown peaks from the herbal mixture makes it extremelydifficult to separate and analyze each individual pharmaceutical activewith required resolution and minimum shift with respect to the knownconcentration of the reference material.

In an embodiment, an herbal combination composition can include:

-   -   a) at least one herbal extract, which can include at least one        extract of:        -   i. Hyssopus officinalis;        -   ii. Zingiber officinale;        -   iii. Viola odorata;        -   iv. Ziziphus jujuba;        -   v. Chamomile;        -   vi. Ocimum tenuiflorum; or        -   vii. A combination of these.    -   b) At least one pharmaceutical composition, which can include:        -   i. Dextromethorphan;        -   ii. Guaifenesin;        -   iii. Acetaminophen;        -   iv. Phenylephrine, such as Phenylephrine hydrochloride;        -   v. Diphenhydramine, such as Diphenhydramine hydrochloride;            and optionally at least one or a combination of    -   c) At least one chelating agent, such as Polyethylene glycol;    -   d) Poloxamer;    -   e) Xanthan gum;    -   f) An antioxidant, which can include Propyl gallate;    -   g) An Acetate buffer solution;    -   h) Coloring ingredients;    -   i) Flavoring ingredients; and    -   j) Sweeteners.

In related embodiments, the herbal extracts can include powder extracts,solvent extracts, and/or essential oil extracts.

In related embodiments, the herbal combination composition can beprovided in a packet size as a liquid, mixture, or powder; in liquid,capsule or tablet dosage forms; wherein a tablet, capsule, apredetermined weight of a mixture or powder, or a predetermined liquidvolume are defined as a single dosage.

In related embodiments, a liquid single-dosage formulation of the herbalcombination composition can be 5 ml (1 teaspoon), 10 ml (2 teaspoons),15 ml (3 teaspoon), or 20 ml (4 teaspoon) of the final formulationpackage size, 120, 240 ml, or another dosage volume.

In related embodiments, the herbal extracts of the herbal combinationcomposition can be pure extracts with a 4:1 to 6:1 extraction ratiorange.

In related embodiments, the optional coloring ingredients of the herbalcombination composition can include at least one or a combination of:FD&C Green #3, FD&C Yellow #6, FD&C Blue #1, and FDC&C RED #40.

In related embodiments, the optional flavoring ingredients of the herbalcombination composition can include at least one or a combination of:grape flavor, honey flavor, berry flavor, cherry Flavor, lemon flavor,mango flavor, and strawberry flavor. In further related embodiments, theflavoring ingredients can comprise no more than 2% by volume of asingle-dosage volume of the herbal combination composition.

In a related embodiment, an herbal combination composition, as specifiedin percentage of total volume of 240 ml of the herbal combinationcomposition and in specific volume, can include:

-   -   1) Viola odorata extract in 1% by volume or 2.4 ml;    -   2) Hyssop extract in 1% by volume or 2.4 ml;    -   3) Ocimum tenuiflorum (Tulasi) extract liquid 1:10 in 0.5% by        volume or 1.2 ml;    -   4) Jujube extract in 0.5% by volume or 1.2 ml;    -   5) Ginger extract in 1.04% by volume or 2.5 ml;    -   6) Menthol in 0.05% by volume or 0.12 ml;    -   7) Chamomile in 0.521% by volume or 1.25 ml;    -   8) Polyethylene glycol 600 to 1000 in 5% by volume or 12 ml;    -   9) Sucralose in 0.4% by volume or 0.96 ml;    -   10) Dextromethorphan in range of 5-20 milligram;    -   11) Glycerine in 5% by volume or 12 ml;    -   12) Propylene glycol in 3% by volume or 7.2 ml;    -   13) Polaxamer, which can be Polaxamer 407 in 0.208% by volume or        0.5 ml;    -   14) Ethylenediaminetetraacetic acid (EDTA) in 0.2% by volume or        0.48;    -   15) Methylparaben in 0.018% by volume or 0.043 ml;    -   16) Potassium sorbate in 0.1% by volume or 0.24 ml;    -   17) Propylparaben in 0.02% by volume or 0.048 ml;    -   18) Cherry flavor/Any other suitable flavor agent in 1% by        volume or 2.4 ml    -   19) Sorbitol in 2.5% by volume or 6 ml;    -   20) Xanthan gum in 0.075% by volume or 0.18 ml;    -   21) Saccharin in 0.02% by volume or 0.048 ml;    -   22) Citric acid in 5% by volume or 12 ml;    -   23) Guaifenesin in a range of 50-400 milligram;    -   24) Acetaminophen in a range of 160-650 milligram;    -   25) Phenylephrine HCl in a range of 2.5-10 milligram;    -   26) Sorbitol in 5% by volume or 12 ml;    -   27) Diphenhydramine HCl in a range of 6.25-50 milligram;    -   28) FD&C Green in 0.00125% by volume or 0.003 ml;    -   29) Purified acetate buffered water; in volume to reach total        volume of 240 ml; and/or    -   30) Anhydrous citric Acid 0.05-0.1% to adjust pH to target        value.

In a further related embodiment, the herbal combination composition canfurther include sucrose, as a substitute for or in addition to Saccharinand/or Sorbitol.

In a further related embodiment, the herbal combination composition canfurther include sucralose, as a substitute for or in addition toSaccharin and/or Sorbitol.

In a related embodiment, the herbal combination composition in asingle-dosage formulation can include at least one or a combination of:

-   -   1) Viola odorata extract in a range of 0.25%-1.5% by volume;    -   2) Hyssop extract in a range of 0.25%-1.5% by volume;    -   3) Tulasi extract liquid 1:10 in a range of 0.25%-0.75% by        volume;    -   4) Jujube extract in a range of 0.25%-1% by volume;    -   5) Ginger extract in a range of 0.25%-1.56% by volume;    -   6) Menthol extract in a range of 0.025%-0.075% by volume;    -   7) Chamomile extract in a range of 0.25%-1% by volume;    -   8) Polyethylene glycol 1000 in a range of 2.5%-7.5% by volume;    -   9) Sucralose in a range of 0.2%-0.6% by volume;    -   10) Dextromethorphan in a range of 5-20 mg;    -   11) Glycerine in a range of 2.5%-7.5% by volume;    -   12) Propylene glycol in a range of 1.5%-4.5% by volume;    -   13) Polaxamer, which can be Polaxamer 407 in a range of        0.1%-0.325% by volume;    -   14) eDTA in a range of 0.1%-0.3% by volume;    -   15) Methylparaben in a range of 0.009%-0.03% by volume;    -   16) Potassium sorbate in a range of 0.05%-0.15% by volume;    -   17) Propylparaben in a range of 0.01%-0.03% by volume;    -   18) Cherry flavor/Any other suitable flavor agent in a range of        0.5%-1.5% by volume;    -   19) Sorbitol in a range of 1.2%-3.8% by volume;    -   20) Xanthan gum in a range of 0.038%-0.113% by volume;    -   21) Saccharin in a range of 0.01%-0.03% by volume;    -   22) Citric acid in a range of 2.5%-7.5% by volume;    -   23) Guaifenesin in a range of 50-400 mg;    -   24) Acetaminophen in a range of 160-650 mg;    -   25) Phenylephrine HCl in a range of 2.5-10 mg;    -   26) Sorbitol in a range of 2.5%-7.5% by volume;    -   27) Diphenhydramine HCl in a range of 6.25-50 mg;    -   28) Propyl Gallate in a range of 0.05%-0.2% by volume;    -   29) FD&C Green Grape flavor in a range of 0.001%-0.002% by        volume;    -   30) Anhydrous citric Acid in a range of 0.038%-0.113% by volume;        and/or    -   31) Purified acetate buffered water in a range of 32%-96% by        volume;    -   wherein ingredient ranges, if not specified by weight or volume,        are listed in percentage by volume of the herbal combination        composition for a single-dosage formulation of the herbal        combination composition.

In some embodiments, herbal combination composition can includepropylene glycol in a range of 1.5%-14% in percentage of total volume ofthe herbal combination composition. In further related embodiments, ahigher content of propylene glycol, up to 14% by volume and in somecases higher, can serve to increase the stability when acetaminophen(APAP) is included as an ingredient.

In related embodiments, the herbal combination composition in asingle-dosage formulation can include at least one or a combination of:

-   -   1) Viola odorata extract in a range of 0.25%-1.5% by weight;    -   2) Hyssop extract in a range of 0.25%-1.5% by weight;    -   3) Tulasi extract liquid 1:10 in a range of 0.25%-0.75% by        weight;    -   4) Jujube extract in a range of 0.25%-1% by weight;    -   5) Ginger extract in a range of 0.25%-1.5% by weight;    -   6) Menthol extract in a range of 0.022%-0.075% by weight;    -   7) Chamomile extract in a range of 0.25%-1% by weight;    -   8) Polyethylene glycol 600-1000 in a range of 2.5%-8% by weight;    -   9) Sucralose in a range of 0.2%-1% by weight;    -   10) Dextromethorphan in a range of 5-20 mg;    -   11) Glycerine in a range of 2.5%-9% by weight;    -   12) Propylene glycol in a range of 1.5%-4.5% by weight;    -   13) Polaxamer, which can be Poloxamer 407 in a range of        0.1%-0.3% by weight;    -   14) eDTA in a range of 0.1%-0.3% by weight;    -   15) Methylparaben in a range of 0.01%-0.04% by weight;    -   16) Potassium sorbate in a range of 0.05%-0.2% by weight;    -   17) Propylparaben in a range of 0.01%-0.03% by weight;    -   18) Cherry flavor/Any other suitable flavor agent in a range of        0.5%-1.5% by weight;    -   19) Sorbitol in a range of 1.2%-5.5% by weight;    -   20) Xanthan gum in a range of 0.04%-0.165% by weight;    -   21) Saccharin in a range of 0.01%-0.03% by weight;    -   22) Citric acid in a range of 2.5%-12% by weight;    -   23) Guaifenesin in a range of 50-400 mg;    -   24) Acetaminophen in a range of 160-650 mg;    -   25) Phenylephrine HCl in a range of 2.5-10 mg;    -   26) Sorbitol in a range of 2.5%-11% by weight;    -   27) Diphenhydramine HCl in a range of 6.25-50 mg;    -   28) FD&C Green Grape flavor in a range of 0.001%-0.002% by        weight;    -   29) Propyl Gallate in a range of 0.05%-0.2% by weight;    -   30) Anhydrous citric Acid in a range of 0.038%-0.18% by weight;        and/or    -   31) Purified acetate buffered water in a range of 30%-96% by        weight;    -   wherein ingredient ranges, if not specified by weight, are        listed in percentage by weight of the herbal combination        composition for a single-dosage formulation of the herbal        combination composition.

In related embodiments, the herbal combination composition in asingle-dosage formulation can include at least one or a combination of:

-   -   1) Viola adorta extract in a range of 1.2-3.6 gram;    -   2) Hyssop extract in a range of 1.2-3.6 gram;    -   3) Tulasi extract liquid 1:10 in a range of 0.6-1.8 gram;    -   4) Jujube extract in a range of 0.6-1.8 gram;    -   5) Ginger extract in a range of 1.25-3.75 gram;    -   6) Menthol in a range of 0.0534-0.1602 gram;    -   7) Chamomile extract in a range of 0.625-1.875 gram;    -   8) Polyethylene glycol 600-1000 in a range of 6.6-19.8 gram;    -   9) Sucralose in a range of 0.8112-2.4336 gram;    -   10) Dextromethorphan in a range of 0.005-0.02 gram;    -   11) Glycerine in a range of 7.554-22.662 gram;    -   12) Propylene glycol in a range of 3.47508-10.42524 gram;    -   13) Polaxamer, which can be Polaxamer 407, in a range of        0.25-0.75 gram;    -   14) eDTA in a range of 0.2064-0.6192 gram;    -   15) Methyl paraben in a range of 0.02967-0.08901 gram;    -   16) Pottasium sorbate in a range of 0.1632-0.4896 gram;    -   17) Propyl paraben in a range of 0.02544-0.07632 gram;    -   18) Cherry flavor/Any other suitable flavor agent in a range of        1.2-3.6 gram;    -   19) Sorbitol in a range of 4.47-13.41 gram;    -   20) Xanthan gum in a range of 0.135-0.405 gram;    -   21) Saccharin in a range of 0.019872-0.059616 gram;    -   22) Citric acid in a range of 9.96-29.88 gram;    -   23) Guafanesin in a range of 0.05-0.4 gram;    -   24) Acetaminophen in a range of 0.16-0.65 gram;    -   25) Phenylephrine HCl in a range of 0.0025-0.01 gram;    -   26) Sorbitol in a range of 8.94-26.82 gram;    -   27) Diphenhydramine in a range of 0.00625-0.05 gram;    -   28) FD&C Green Grape flavor in a range of 0.0015-0.0045 gram;    -   29) Propyl Gallate in a range of 0.145-0.45 gram;    -   30) Anhydrous citric Acid in a range of 0.1494-0.4482 gram;    -   31) Purified acetate buffered water in a range of 76.686-230.058        gram.

In an embodiment, a method for manufacture of an herbal combinationcomposition 100, as shown in FIG. 1, can include, all or a combinationof:

-   -   a) Ingredient preparation 110, including:        -   1) Weighing of herb extracts 111;        -   2) Sieving of herbs to mesh 112;        -   3) Weighing of active pharmaceutical ingredients 116;    -   b) Preparing acetate buffer 120, which includes preparation of        enough acetate buffer to mix and dissolve extracts and active        pharmaceuticals, use for make-up volume, and use for dilution of        the solution under manufacture;    -   c) Dissolving herbal extracts 130, wherein the extracts are        dissolved and mixed with 50% volume of the acetate buffer at 35°        C., with gentle stirring for a predetermined period, which can        be one hour, or between 15 minutes and 3 hours;    -   d) Filtering solution 132, wherein the solution is filtered, for        example with a cartridge filter, which can be a 0.5 micron        cartridge filter;    -   e) Adding water soluble inactive ingredients 134;    -   f) Adding poloxamer 136, wherein crushed poloxamer is added to        the solution during continuing stirring,    -    wherein the crushed poloxamer is made by grinding poloxamer        beads into small particles,    -    wherein the poloxamer is selected from the group of nonionic        triblock copolymers composed of a central hydrophobic chain of        polyoxypropylene (poly(propylene oxide)) flanked by two        hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), or        a composition of these;    -   g) Add sorbitol, potassium sorbate, and sucralose to stirring        extract solution;    -   h) Add oil soluble propyl paraben 138, which is dissolved in        mixture of propylene glycol and glycerin;    -   i) Add Saccharin and ethylenediaminetetraacetic acid (EDTA);    -   j) Adding acetaminophen 140, by raising temperature to 45° C.,        or 40° C.-50° C., and continuing brisk agitation, while adding        acetaminophen in 3 parts until all parts are dissolved. Use high        shear mixer to homogenize solution;    -   k) Adding Polyethylene Glycol 142 during high shear mixing, such        that the Polyethylene Glycol, for example as PEG 600-1000, is        pre-melted, for example in water jacketed vessel;    -   l) Adding Dextromethorphan, Guaifenesin, diphenhydramine HCl,        Phenylephrine HCl 144, as per a pre-determined single-dosage        formulation and stir and dissolve for 45 minutes, or 15-75        minutes, at 40° C., or 35° C.-45° C., and then adding another        30% of the acetate buffer;    -   m) Adding coloring and flavoring agents 146 148. If foaming        occurs, add Tween 80;    -   n) Dissolving and adding menthol. This can be done during or        after adding coloring and flavoring 146 148;    -   o) Adding xanthan gum gel 150 with brisk stirring, wherein the        xanthan gum gel is made by dissolving xanthan gum in water;    -   p) Adding acetate buffer to produce the final target volume;    -   q) Check the Ph;    -   r) Adjusting pH 152 to a target Ph value by using USP anhydrous        citric acid, such that the target Ph can be in a range of        4.9-5.3, 5.0-5.2, or about 5.1 Ph; and    -   s) Checking final viscosity 154.

In a related embodiment, an UV/HPLC spectroscopic gradient method caninclude:

-   -   a) In a mobile phase C: mixing 80% of water with 20% methanol,        triethylamine 0.1%, and adjust pH with phosphoric acid to 3.    -   b) In a mobile phase D (for final volume of 500 ml): dissolving        0.55 grams of 1 octane sulfonic acid in 50 ml of water, then        filtering it, adding 250 ml of HPLC grade water, add 0.1% TEA        (trimethylamine), then adding MeCN (acetonitrile) to reach a        final volume of 500 ml. Finally, adjusting pH to 3 using        phosphoric acid;    -   wherein references of active components are made in 10%        methanol. Test solutions are diluted to the same reference        strengths compared to active references for a direct peak height        or area ratio calculation, thus allowing determination whether        the test solution's active ingredient is within 90% to 110% of        the active reference. A gradient method starting at 1.5        ml/minute flow rate of the combination of C:D (20:80) at the        detection wavelength of 264 and changing to flow rate to 1.0 and        the detection wavelength to 214 at 4 minutes time is followed        and executed with an automated data and equipment        control/acquisition system. The method elucidates all peaks        within 15 minutes and is ready for next injection after a needle        purge.    -   A Phenomenox™ brand column Luna® 5 μm C18(2) 100 Å, LC Column        250×4.6 mm can for example be used and maintained at 28° C.

In related testing of embodiments of the herbal combination composition,Phenylephrine HCl test samples and reference concentrations peak areaswere found to be within a normal acceptance criteria range.

In related testing of embodiments of the herbal combination composition,Guaifenesin test samples and reference concentrations peak areas werefound to be within a normal acceptance criteria range.

In related testing of embodiments of the herbal combination composition,Acetaminophen test samples and reference concentrations peak areas werefound to be within a normal acceptance criteria range.

In related testing of embodiments of the herbal combination composition,Dextromethorphan test samples and reference concentrations peak areaswere found to be within a normal acceptance criteria range.

In related testing of embodiments of the herbal combination composition,Diphenhydramine test samples and reference concentrations peak areaswere found to be within a normal acceptance criteria range.

In related testing of embodiments of the herbal combination composition,no microbial growth was shown in formulations with and withoutDiphenhydramine. Microbial growth was observed in the +Ve control plateat the end of USP defined incubation period and temperature.

Here has thus been described a multitude of embodiments of the herbalcombination composition, and methods related thereto, which can beemployed in numerous modes of usage.

The many features and advantages of the invention are apparent from thedetailed specification, and thus, it is intended by the appended claimsto cover all such features and advantages of the invention, which fallwithin the true spirit and scope of the invention.

Many such alternative configurations are readily apparent, and should beconsidered fully included in this specification and the claims appendedhereto. Accordingly, since numerous modifications and variations willreadily occur to those skilled in the art, it is not desired to limitthe invention to the exact construction and operation illustrated anddescribed, and thus, all suitable modifications and equivalents may beresorted to, falling within the scope of the invention.

What is claimed is:
 1. An herbal combination composition, comprising: a)herbal extracts comprising the combination of: Hyssopus officinalis;Zingiber officinale; Viola odorata; Ziziphus jujuba; chamomile; andOcimum tenuiflorum; and b) at least one pharmaceutical composition,comprising: dextromethorphan in the range of 5-20 milligram;acetaminophen in the range of 160-650 milligram; and phenylephrinehydrochloride in the range of 2.5-10 milligram.
 2. The herbalcombination composition of claim 1, wherein the at least one herbalextract comprises: a) the Viola odorata in a percentage by volume of theherbal combination composition range of 0.5%-1.5%; b) the Hyssopusofficinalis in a percentage by volume of the herbal combinationcomposition range of 0.5%-1.5%; c) the Ocimum tenuiflorum in apercentage by volume of the herbal combination composition range of0.25%-1%; d) the Ziziphus jujuba in a percentage by volume of the herbalcombination composition range of 0.25%-1%; e) the Zingiber officinale ina percentage by volume of the herbal combination composition range of0.5%-1.56%; and f) the chamomile in a percentage by volume of the herbalcombination composition range of 0.25%-1%.
 3. The herbal combinationcomposition of claim 1, further comprising: polyethylene glycol in apercentage by volume of the herbal combination composition range of2.5%-7.5%; wherein the polyethylene glycol has a molecular weight of500-1500 g/mol.
 4. The herbal combination composition of claim 1,further comprising: propylene glycol in a percentage by volume of theherbal combination composition range of 1.5%-14.5%.
 5. The herbalcombination composition of claim 1, further comprising: polaxamer 407 ina percentage by volume of the herbal combination composition range of0.1%-0.3%.
 6. The herbal combination composition of claim 1, furthercomprising: ethylenediaminetetraacetic acid in a percentage by volume ofthe herbal combination composition range of 0.1%-0.3%.
 7. The herbalcombination composition of claim 1, further comprising: methyl parabenin a percentage by volume of the herbal combination composition range of0.009%-0.027%.
 8. The herbal combination composition of claim 1, furthercomprising: potassium sorbate in a percentage by volume of the herbalcombination composition range of 0.05%-0.15%.
 9. The herbal combinationcomposition of claim 1, further comprising: propyl paraben in apercentage by volume of the herbal combination composition range of0.01%-0.03%.
 10. The herbal combination composition of claim 1, furthercomprising: xanthan gum in a percentage by volume of the herbalcombination composition range of 0.038%-0.113%.
 11. The herbalcombination composition of claim 1, further comprising: citric acid in apercentage by volume of the herbal combination composition range of2.5%-7.5%.
 12. The herbal combination composition of claim 1, furthercomprising: propyl gallate in a percentage by volume of the herbalcombination composition range of 0.05%-0.2%.
 13. The herbal combinationcomposition of claim 1, further comprising: anhydrous citric acid in apercentage by volume of the herbal combination composition range of0.038%-0.113%.
 14. The herbal combination composition of claim 1,further comprising: purified acetate buffered water in a percentage byvolume of the herbal combination composition range of 32%-96%.
 15. Theherbal combination composition of claim 1, wherein the at least onepharmaceutical composition comprises: a) the dextromethorphan in rangeof 5-20 milligram; b) guaifenesin in a range of 50-400 milligram; c) theacetaminophen in a range of 160-650 milligram; d) phenylephrinehydrochloride in a range of 2.5-10 milligram; and e) diphenhydraminehydrochloride in a range of 6.25-50 milligram.
 16. An herbal combinationcomposition, comprising: a) herbal extracts comprising the combinationof: Viola odorata in a percentage by volume of the herbal combinationcomposition range of 0.5%-1.5%; Hyssopus officinalis in a percentage byvolume of the herbal combination composition range of 0.5%-1.5%; Ocimumtenuiflorum in a percentage by volume of the herbal combinationcomposition range of 0.25%-1%; Ziziphus jujuba in a percentage by volumeof the herbal combination composition range of 0.25%-1%; Zingiberofficinals in a percentage by volume of the herbal combinationcomposition range of 0.5%-1.56%; and chamomile in a percentage by volumeof the herbal combination composition range of 0.25%-1%; and b) at leastone pharmaceutical composition, comprising: dextromethorphan;acetaminophen; and phenylephrine.